Rina Nakajima1, Tomomitsu Miyagaki2, Hiroaki Kamijo1, Tomonori Oka1, Naomi Shishido-Takahashi3, Hiraku Suga1, Makoto Sugaya3, Shinichi Sato1. 1. Department of Dermatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. 2. Department of Dermatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. Electronic address: asahikari1979@gmail.com. 3. Department of Dermatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Department of Dermatology, International University of Health and Welfare, Chiba, Japan.
Abstract
BACKGROUND: Galectin-9, a member of the galectin family, can promote tumor growth through inducing apoptosis in anti-tumor immune cells via T cell immunoglobulin and mucin domain 3 (TIM-3). On the other hand, galectin-9 also induces tumor cell apoptosis in many malignancies and thought to have potential as an anti-cancer agent. OBJECTIVE: To examine the expression and therapeutic applicability of galectin-9 in cutaneous T-cell lymphoma (CTCL). METHODS: Galectin-9 expression in lesional skin and sera was measured using CTCL samples. The effect of galectin-9 on CTCL cell lines was investigated in vitro. We also examined effect of galectin-9 on tumor growth of CTCL cells in immune-deficient mice. Moreover, we examined the efficacy of galectin-9, anti-TIM-3 blocking antibody, or their combination on tumor growth of EL-4 cells in wild-type mice. RESULTS: Galectin-9 was expressed on tumor cells in lesional skin of CTCL and the expression levels were associated with decreased CD8+ T-cell infiltration. Serum galectin-9 levels were correlated with disease severity markers. High-dose galectin-9 induced cell death of CTCL cell lines through activation of caspase-3 and caspase-9, independently of TIM-3. High-dose galectin-9 suppressed the growth of CTCL cells and EL-4 cells in vivo. Furthermore, additional anti-TIM-3 blocking antibody administration to galectin-9 achieved greater inhibition of tumor growth compared to single administration. CONCLUSION: Galectin-9 expression on tumor cells may be associated with CTCL progression through attenuating anti-tumor immunity. On the other hand, exogenous high-dose galectin-9 administration can be a therapeutic strategy for CTCL and anti-TIM-3 blocking antibody can augment the efficacy of galectin-9.
BACKGROUND:Galectin-9, a member of the galectin family, can promote tumor growth through inducing apoptosis in anti-tumor immune cells via T cell immunoglobulin and mucin domain 3 (TIM-3). On the other hand, galectin-9 also induces tumor cell apoptosis in many malignancies and thought to have potential as an anti-cancer agent. OBJECTIVE: To examine the expression and therapeutic applicability of galectin-9 in cutaneous T-cell lymphoma (CTCL). METHODS:Galectin-9 expression in lesional skin and sera was measured using CTCL samples. The effect of galectin-9 on CTCL cell lines was investigated in vitro. We also examined effect of galectin-9 on tumor growth of CTCL cells in immune-deficient mice. Moreover, we examined the efficacy of galectin-9, anti-TIM-3 blocking antibody, or their combination on tumor growth of EL-4 cells in wild-type mice. RESULTS:Galectin-9 was expressed on tumor cells in lesional skin of CTCL and the expression levels were associated with decreased CD8+ T-cell infiltration. Serum galectin-9 levels were correlated with disease severity markers. High-dose galectin-9 induced cell death of CTCL cell lines through activation of caspase-3 and caspase-9, independently of TIM-3. High-dose galectin-9 suppressed the growth of CTCL cells and EL-4 cells in vivo. Furthermore, additional anti-TIM-3 blocking antibody administration to galectin-9 achieved greater inhibition of tumor growth compared to single administration. CONCLUSION:Galectin-9 expression on tumor cells may be associated with CTCL progression through attenuating anti-tumor immunity. On the other hand, exogenous high-dose galectin-9 administration can be a therapeutic strategy for CTCL and anti-TIM-3 blocking antibody can augment the efficacy of galectin-9.
Authors: Denis Miyashiro; Bruno de Castro E Souza; Marina Passos Torrealba; Kelly Cristina Gomes Manfrere; Maria Notomi Sato; José Antonio Sanches Journal: Int J Mol Sci Date: 2022-01-15 Impact factor: 5.923